Glycolipid derivatives of vancomycin are active against vancomycin-resistant bacterial strains, and thus provide a starting point for the design of better antibiotics. Using a combination of chemical, biochemical, and genetic approaches, this laboratory has obtained evidence that these vancomycin derivatives have two different modes of action. One mode of action is shared with the parent compound, vancomycin, and involves binding to the peptide termini of peptidoglcyan precurosors, sterically blocking the enzymes involved in peptidoglycan synthesis. The second mode of action, attributable to the functionalized carbohydrate portion of the molecules, also involves inhibition of peptidoglycan synthesizing enzymes, but does not depend on peptide binding. Instead, the functionalized carbohydrates directly inhibit bacterial transglycosylases. This latter mode of action may explain the activity against resistant bacterial strains. If so, one might predict that better antibiotics can be made by coupling a compound having transglycosylase inhibitory activity to a compound having peptide binding activity.
The first aim of this grant is to investigate the requirements for structural activity of the best transglycosylase inhibitor currently known, the pentasaccharide moenomycin A.
The second aim i s to explore the potential of hybrid antibiotics consisting of a peptide binding element coupled to a transglycosylase inhibitory element.
The third aim i nvolves developing a better understanding of the regulatory networks involved in transglycosylation by probing bacterial strains with the compounds that are produced. Since transglycosylation is important for both growth and division of bacterial cells, understanding these networks may shed light on fundamental aspects of bacterial metabolism.
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